| As an important organic acid in nature, shikimic acid(SA) has been widely existed in various plant tissues, such as illicium verum. Due to the multiple biological activities of anti-inflammatory, analgesic, antioxidant and antibacterial, SA has attracted great interests in pharmaceutical area in recent years. However, the poor absorption effect in vivo and the burst release limited its clinical application. In this study, we were attempting to combined the advantages of coaxial-electrospray technique and modern pharmacy, modern testing technology to investigate the SA-loaded microencapsulation for sustained release and enhanced bioavailability.Part One: ReviewsThis part mainly reviewed the research progress of electrospray technique in nano drug delivery system, as well as the development. Additionally, the research status of SA, as well as its pharmacological action were also describe in this section. Moreover, the topic basis and research approach were presented, thus providing a foundation for the development of the work.Part Two: Rreformulation studiesA high-performance liquid chromatography(HPLC) method was established to determine the content of SA in in vitro samples. And the HPLC methodology was turned to be in good specificity and high sensitivity with a linear range of 0.5~50 μg/m L. In addition, both the inter-day and intra-day precision were less than 3%. The samples were found in good stability in 72 h with the recovery between 98% and 101%. The oil-water partition coefficient of SA in double distilled water and p H 1.2 HCl solution were confirmed as-1.49,-1.12, indicating the drug was not easily absorbed by gastrointestinal tract.Part Three: Preparation of SA-loaded electrospray nanoparticles as well as its dissolution testBased on single factor study, the SA-loaded electrospray nanoparticles were successfully prepared, and the optimum conditions were confirmed as:acetone/methanol(solvent), polylactic acid(carrier) with drug loaded ratio of 1:3. Moreover, the optimal parameters were determined as follows: The voltage was 18 KV with a flow rate of 0.3 m L/h and the collection distance was15 cm with a stainless needle being 0.5mm. As shown in SEM images, SA-loaded electrospray nanoparticles were appeared as irregular spherical shape with the mean particle size being around 600 nm. The prepared electrospray nanoparticle appeared as amorphous forms with a characteristic hump, indicating that SA was no longer presented as a crystalline material in the carrier. The in vitro release study demonstrated that the prepared electrospray nanoparticle could slightly retard the drug dissolution rate, but not react well in controlling the release.Part Four: Preparation of SA-loaded coaxial-electrospray nanoparticles as well as its dissolution testIn this section, the SA-loaded coaxial-electrospray nanoparticles were successfully prepared, and the optimum conditions were confirmed as : phospholipid(sheath material), voltage of 21 KV, distance in 15 cm, the needle size of 0.5 mm with a flow rate of sheath solution and core solution being 0.3m L/min, respectively. According to the results of SEM analysis, the SA coaxial-electrospray nanoparticles displayed spherical or ellipsoidal shape with particle size more than 600 nm. The results of dissolution test demonstrated that the coaxial-electrospray nanoparticles could reduce burst release effect of SA, thus presenting a sustained release manner. The drug release of prepared nanoparticles was turned to be Fickian diffusion as shown in drug release mechnism study.Part Five: Intestinal absorption of electrospray nanoparticles in ratIn this section, a high-performance liquid chromatography(HPLC) method was established to determine the content of SA in perfusion solution. The HPLC methodology was turned to be in good specificity and high sensitivity with good drug stability. Theabsorption of SA in the intestinal tract,studied using an in situ perfusion method inrats,also revealed jejunum asthe main absorptive segment followed by duodenum and ileum. Moreover, the SA-loaded nanoparticles greatly enhanced the absorption of SA in the tested intestinal segments. The intestinal absorption rate was not enhanced with increasing drug concentration(5-15 μg/m L) which suggested that active transport orfacilitated diffusion could play vital role in SA absorption.Moreover, the coaxial-electrospray nanoparticles promoted the absorption of more SA in the intestinal segments. This result could be imputed to the addition of phospholipid, which might have contributed to an increased permeability of the intestinal membrane or improved affinity between lipid particles and the intestinal membrane.Part Six: Pharmacokinetic study of electrospray nanoparticles in ratIn this section, a high-performance liquid chromatography(HPLC) method was established to determine the content of SA in plasma samples. The HPLC methodology was turned to be in good specificity, high recovery and inter-day or intra-day precision. The results of pharmacokinetic study in vivo indicated that significant differences were observedin SA electrospray nanoparticles after oral administration with delayed t1/2(5.40 ± 1.38 h vs. 7.58 ± 1.11 h), MRT(5.61± 0 h vs.7.96 ± 0.66 h) and higher Cmax(603.91 ± 46.40 vs.5642.80 ±150.13 ng/m L), compared with free drug. It was obviously shown that the AUC0-24 hwas enhanced from 3021.80 ± 305.83 to 42062.89 ± 1602.35 hng/m L, which implied that the relative oral bioavailability of F-ES was 13.9-fold greater than free drug. Inthe case of coaxial-electrospray nanoparticles, marginal decrease in Cmax(4913.82 ± 315.96ng/m) and AUC0-24 h were recorded as compared to SA electrospray nanoparticles, while a delayed Tmax(6 h) was observed. Taken together, the SA-loaded coaxial-electrospray nanoparticle exhibited a sustained release manner with enhanced bioavailability after oral administration. |
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